PROJECT SUMMARY/ABSTRACT Rhinovirus (RV) infections frequently cause colds, and yet these viruses also contribute to lower respiratory infections in young children and the elderly, and to 50-90% of asthma exacerbations. Moreover, RV associated wheezing illnesses in preschoolers are strong risk factors for developing asthma. The lack of specific treatments for more severe RV illnesses and exacerbations of asthma is a major unmet medical need. What determines the severity of illness caused by RV infections? This is a key question, since it is the severe colds that cause exacerbations in patients with asthma and increase the risk of recurrent wheeze and asthma in preschoolers. We propose that factors related to the virus (RV species), host (RV receptor genetics, innate immune response), and environment (the farm microbiome) strongly influence the severity of illness associated with RV infection. Our highly interactive program consisting of 2 projects and 2 cores will define mechanisms of susceptibility vs. resistance to severe viral respiratory illnesses (VRI). The clinical centerpiece of the program is the Wisconsin Infant Study Cohort (WISC) (Project I), a unique dairy farm birth cohort designed to investigate links between farm exposures, immune maturation, and infectious and allergic respiratory disease. The cohort is now fully enrolled, and our preliminary data suggest that farm exposures reduce both VRI and atopic dermatitis, two important risk factors for asthma. We now hypothesize that farming microbial exposures and unique patterns of microbial colonization in early life alter of innate and T regulatory development, which lead to protection from VRI and allergic diseases. To test this hypothesis, we will follow current WISC participants to age 4-8 years, and recruit additional farm and non-farm newborns (50/group) who will be monitored with new technologies to better define early life microbial exposures and immune development. We have established relationships with the Wisconsin Amish community, who have very low rates of allergic diseases, and will include 50 Amish newborns in the new recruits. Project II will focus on interactions between the RV C species (RV-C) and cadherin related protein-3 (CDHR3) on host airway epithelial cells. RV-C are linked to more severe illnesses and severe exacerbations of asthma, but little is known about RV-C pathogenesis. Our recent work has greatly advanced this cause by developing novel molecular tools, culture and production techniques, identifying the first cell surface receptor, and determining the 3D molecular structure for RV-C. In the current proposal for Project II, we will conduct experiments to further define RV-C structure, the biochemistry of interactions with CDHR3, and genetic and biochemical mechanisms regulating the subcellular expression and function of CDHR3. Understanding the virus capsid and interactions with CDHR3 would provide two new targets for small molecule RV-C antivirals. Ultimately, this information will lead to new strategies for the treatment of prevention of VRI and respiratory allergies in children.